TY - JOUR
T1 - Sortilin regulates progranulin action in castration-Resistant prostate cancer cells
AU - Tanimoto, Ryuta
AU - Morcavallo, Alaide
AU - Terracciano, Mario
AU - Xu, Shi Qiong
AU - Stefanello, Manuela
AU - Buraschi, Simone
AU - Lu, Kuojung G.
AU - Bagley, Demetrius H.
AU - Gomella, Leonard G.
AU - Scotlandi, Katia
AU - Belfiore, Antonino
AU - Iozzo, Renato V.
AU - Morrione, Andrea
N1 - Publisher Copyright:
© 2015 by the Endocrine Society.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - The growth factor progranulin is as an important regulator of transformation in several cellular systems.Wehave previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low evels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 andDU145cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression.
AB - The growth factor progranulin is as an important regulator of transformation in several cellular systems.Wehave previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low evels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 andDU145cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression.
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U2 - 10.1210/en.2014-1590
DO - 10.1210/en.2014-1590
M3 - Article
C2 - 25365768
AN - SCOPUS:84919742882
SN - 0013-7227
VL - 156
SP - 58
EP - 70
JO - Endocrinology
JF - Endocrinology
IS - 1
ER -
